Saccharides from bacteria have been used for many years in vaccines. As saccharides are T-independent antigens, however, they are poorly immunogenic. In addition, they are ineffective in infants or toddlers under 2 years old. Conjugation to a carrier can effectively convert T-independent antigens into T-dependent antigens, thereby enhancing memory responses and allowing protective immunity to develop. To date, the most effective saccharide vaccines are therefore based on glycoconjugates. WO95/31994 and WO94/03208 both to Yeda Research and Development Co. Ltd., U.S. Pat. No. 5,204,098 and WO2008/081022 relate to conjugates of poorly immunogenic antigens.
Many conjugation processes make use of short oligosaccharides, and this is mainly for improving the manufacturing process (better control of manufacturing consistency, better characterization of the final product). It is well known that saccharide chain length can have an impact on the immunogenicity of conjugate vaccines (P. Costantino et al. Expert Opin. Drug Discov., 6 (2011) 1045). IN1330MUM2010 to Serum Institute of India Ltd relates to a method of making polysaccharide fragments suitable for conjugation. U.S. Pat. No. 6,045,805 also describes methods for making oligosaccharides.
Typhoid fever remains a serious disease in developing countries which affects millions of people each year (Crump J A et al., Bull. Wld. Hlth. Org. 82, 346-353 (2004); Ochai R L et al. and the Domi Typhoid Study Group, Bull. Wld. Hlth. Org. 86, 260-268 (2008)). In the last decade, conjugate vaccines have been developed for this disease. For instance, a safe and highly immunogenic conjugate vaccine based on Vi (polysaccharide from Salmonella enterica serovar Typhi) and rEPA protein carrier was developed by NICHD/NIH (Lanh et al., N. Eng. J. Med. 2003; Thiem et al., Clin Vac. Immunol. 2011; Szu, Expert Rev. Vaccines 12(11), 1273-1286 (2013)). A number of papers discuss the immunogenicity of Vi, its conjugate vaccines and the Vi chain length considered hitherto optimal (Szu et al., Infection and Immunity, 1989, 3823; Szu et al., Infection and Immunity, 1991, 4555; Szu et al. Infection and Immunity, 1994, 5545; Kossaczka et al., Infection and Immunity, 1999, 5806; Cui et al., Clin. Vaccine Immunol., 17 (2010), 73-79; Micoli et al., Vaccine, 29 (2011), 712-720; An et al., Vaccine, 29 (2011), 7618-23; Rondini et al., Clin. Vaccine Immunol., 18 (2011), 460-68; An et al., Vaccine, 30 (2012), 1023-1028).
More recently, a Salmonella Typhi vaccine conjugate based on Vi from purified Citrobacter freundii sensu lato and CRM197 protein carrier has been described by Micoli et al. Vaccine 2012 and Rondini et al., J. Infect. Dev Ctries, 2012. When tested in humans, Vi-CRM197 conjugate vaccine provided higher anti-Vi antibody responses compared to unconjugated Vi after a single immunisation and at a lower dose (van Damme et al., PlosOne 2011; further results presented at the 81h International Conference on Typhoid Fever and Other Invasive Salmonelloses, Bangladesh, March 2013). However, the anti-Vi response following revaccination was lower than the primary response and anti-Vi persistence was shorter than desired (Bhutta et al. Lancet Infect Dis, 14 (2014) 119).
There is therefore still a need to provide improved conjugate vaccines.